Head and neck cancer (HNC) is the 6 most prevalent cancer in the developed world and is associated with low survival (50%) and high recurrence (30%) rates. In these countries about 25% of HNC are causally associated with infection by oncogenic human papillomavirus (HPV) high-risk (HR) types independent of the other major HNC risk factors, tobacco and alcohol. HPV-associated HNC has been shown to have a survival advantage despite their being diagnosed with more advanced disease characteristics. There is the need for HPV testing as a factor in treatment and management decisions for HPV-associated and HPV-negative cancers and for monitoring relapse by HPV status after treatment. If HPV-HR HNC represents a different disease than HPV-independent HNC, it may require different treatment modalities due to different effects of the viral genes or of other HNC risk factors on the molecular pathways. However, studies have not examined multiple markers of disease in individual patients using the unique expertise of the study Sites involved in this project. The purpose of this grant is to plan an international multicenter research collaboration that will evaluate the feasibility of examining multiple biomarkers on individual HNC patients for HPV and for clinical outcomes. Each Study Site has unique expertise that has advanced the mechanistic understanding of viral (HPV) and/or cellular gene contributions to HPV oncogenesis. In addition, Iowa is an established molecular epidemiology Center of HNC and has the expertise and experience to perform large-scale, international collaborations of HNC. We propose to bring the international expertise together to plan and test protocols that will lead: 1) to combining their novel biomarkers for application to individual patients, and 2) to evaluating their combined use in earlier prediction of clinical outcomes in a subsequent international, molecular epidemiologic investigation. The specific aims of the subsequent international collaborative grant are to: 1) develop, test, and revise. protocols for conducting a molecular epidemiologic study and to compare protocol compliance to, benchmarks at the Multicenter Sites: 2) assess the presence, gene expression, and integration of HPV-HR types in head and neck cancer and common cellular gene alterations, and to correlate these with the clinical course; The results will be evaluated in association with HPV status and expression, other etiologic risk factors for HNC (tobacco, alcohol), and local invasion, metastasis, recurrence and survival; and 3) test whether the detection of HPV presence, expression profiles, or viral load in oral exfoliated cells from HNC patients or the presence of anti-HPV-HR antibodies in HNC patient sera can be used to predict HPV-HR HNCs and the clinical outcomes. This aim is to determine whether there is an easily administered, sensitive biomarker that can predict HPV-HR status in HNC tumors prior to therapy.. [unreadable] [unreadable] [unreadable]